Although the utility of biomarkers in reproductive toxicology is now recognized and biomarkers are being applied by epidemiologists for surveillance of environmental hazards to women's reproductive health, there is still a lack of understanding of those specific agents or classes of agents which may affect female fertility and fetal development. There is also a lack of information on the mechanisms of female reproductive toxicity, even when potential hazards have been identified. Some of the pressing current needs which will be addressed in this Program Project include: 1) to establish relevant experimental systems including whole animal models and in vitro cell and tissue cultures, which can be applied to gain better information on which environmental factors may cause female infertility, implantation failure and abnormal fetal development in humans; 2) to identify biological markers of altered function in the ovary, preimplantation embryo, fetus and reproductive tract which may be predictive of reproductive impairment resulting from exposure to an exogenous agent; 3) to utilize reproductive biomarkers for study of environmental toxicants and for definition of their mechanisms of action at the level of organ systems, and ultimately, at the cell and molecular level; and 4) to apply the results of animal studies to identify new biomarkers for human epidemiology, and to enable interpretation of data with existing biomarkers of reproductive effects in human populations. The overall goals of this Program Project will be to develop sensitive new end points for detection of reproductive toxicity in appropriate animal models, and to utilize the knowledge gained from these animal experiments to gather new human data and to interpret existing data from epidemiological studies of human populations. This approach may enable us to determine the biological target(s) of toxicity following human exposures, and thereby, to identify the source of toxicity when there is a complex environment or multiple exposures. To accomplish these objectives we have assembled a team of 16 investigators representing the primary disciplines which are the focus of this research (reproductive toxicology, epidemiology, reproductive biology, reproductive medicine) as well as related areas (endocrinology, developmental biology, cell biology, molecular biology) which will be critical for support of these studies.